KR20180052130A - Lipoic acid choline ester compositions, and methods for making biocompatible ophthalmic formulations - Google Patents

Abstract

The present invention describes ophthalmic lipoic acid choline ester compositions, and specific methods for making biocompatible formulations of such compositions suitable for the eye.

Description

Lipoic acid choline ester compositions, and methods for making biocompatible ophthalmic formulations

I. FIELD OF THE INVENTION

The present invention relates generally to ophthalmic lipoic acid choline ester compositions, and to biocompatible, stable and non-irritating eye drop formulations. The compositions herein are contemplated as therapy for ocular disorders such as presbyopia, dry eye, cataract, and age-related macular degeneration.

II. BACKGROUND OF THE INVENTION

Lipoic acid choline ester (LACE) is a chemically synthesized derivative of R-alpha-lipoic acid.

Also known as thioxanthic acid, the lipoic acid is an eight carbon fatty acid with a disulfide linking the carbons 6 and 8 to form a 1,2-dithiolane ring. The acid forms an optical isomer, and the isomeric R-alpha-lipoic acid is the most biologically active.

The lipoic acid choline ester (LACE, chemical structure, see FIG. 1 ) was designed to permeate the biological membrane by the introduction of a cationic choline head group. Lipoic acid does not penetrate the cornea, whereas choline ester derivatives of lipoic acid penetrate the cornea and are hydrolyzed by the corneal esterase and transformed into biologically active lipoic acid. LACE has been formulated as an ophthalmic solution to treat presbyopia twice a day.

LACE, a prodrug consisting of lipoic acid and choline, is a special molecule for the treatment of presbyopia. Lipoic acid (LA) is the active ingredient, and the choline head group plays a role in assisting the permeability to the eye. After administration of eye drops, the binding between LA and choline is hydrolyzed by esterase in the tear film and cornea. The glass lipoic acid enters the eye and ultimately reaches the lens. Where it is reduced to dihydro lipoic acid by the endogenous oxydoryldactase and then hydrolyzes the cytosolic protein within the lens cells extending to the surface. This protein cleavage enables the free flow of the cytosol, and the reversal of the oxidation process associated with the age-related rigidity of the lens. Ophthalmic solutions made from LACE are expected to enable near vision control and improve near vision focus in people with presbyopia that is age-related loss of perspective control.

Presbyopia is age-related in focusing on a near object, and this condition is not related to the lens in the microstructure of the lens that loses flexibility in automatically adjusting the focal length and curvature of the lens to focus on visible objects. It is caused by physiological changes. This state is corrected by the correcting lens. It has been reported that lipoic acid choline ester ("LACE") (see, for example, U.S. Patent No. 8,410,462) can restore near vision.

This assertion is supported by in vitro studies demonstrating that lens softening can be induced pharmacologically in human donor lenses using dithiothreitol (DTT), a protein disulfide reducing agent, and in mouse lenses using lipoic acid.

This mechanism of action enables consideration of the treatment of various ocular diseases and disorders. These disorders include, but are not limited to, presbyopia, age-related macular degeneration, cataracts, and dry eye.

The problem of making the LACE formulation problematic is that oxidized species that inhibit the activity of the molecule by opening the dithiolan linkage tend to form and become destabilized. At room temperature, LACE rapidly degrades into oxidized species (see " HPLC Chromatogram of LACE Ophthalmic Solution with Degradation Products ", see Figure 2 ). Even when stored at refrigeration temperatures, rapid oxidation already occurs within one week of storage, impairing the availability of the molecule as a drug product. In order for the LACE ophthalmic solution (also referred to as EV06 ophthalmic solution) to exert its full potential as a drug product, it was important to stabilize the aqueous formulation during storage and during use.

Another issue that makes the development of LACE ophthalmic solutions more difficult is the occurrence of eye surface stimuli observed in vivo in the rabbit stimulation model. The present invention describes unexpected parameters contributing to or causing eye irritation, and methods for eliminating or minimizing these parameters. These parameters were not related to the composition of the formulation or the nature of the drug substance, which is normally associated with or contributes to ocular irritation.

The compositions and methods described herein describe methods for long term stabilization of ophthalmic LACE formulations. In addition, an unexpected discovery of the cause of the stimulation of the LACE formulation formulated under specific process conditions is described. In addition, important process parameters identified as key factors in the creation of the final comfortable LACE ophthalmic solution (EV06 ophthalmic solution) were not clear.

The final process conditions minimized the formation of degraded species and minimized the formation of species contributing to eye irritation.

III. Description of Drawings
Figure 1 : Chemical structure of lipoic acid choline ester.
Figure 2 : LACE micelle species, formulation KW-LACE-01-86-2 at 8.1 min for 1, 3 and 4 hour blending.
Figure 3 : LACE micelle species, formulation KW-LACE-01-86-2 at 8.1 min for 6, 8 and 24 hour blending.
Figure 4 : Micellar LACE species (peaks indicated by arrows) are highest when mixed at refrigeration temperature.
Figure 5a : High micelle LACE concentration (indicated by a large peak of 7.9-8.5 min for HPLC) correlates with the "chunked" LACE chloride API.
Figure 5b : Low micelle LACE (peak indicated by arrow) correlates with the lumpless LACE API.
Figure 6 : Effect of alanine and pH.
Figure 7 is a plot of the formulation comparing the following variables: (a) control (original) versus control + 0.25% sodium chloride, control + 0.25% sodium chloride, glycerin free; (b) control (original) versus benzalkonium chloride BAC) -free control, (c) control (original) versus glycerin-free original formulation.
Figure 8 shows the effect of sulfite on LACE stability at < RTI ID = 0.0 > 57 C. < / RTI > Sulfite-containing formulations were prepared at pH 4 and 4.5 at concentrations of 0.05% sulfite (?,?) And 0.1% sulfite (x). The sulfite addition did not stabilize the original formulation ().
Figure 9 further analyzes the potential stabilizing effect of benzalkonium chloride removal. All formulation variants that did not contain benzalkonium chloride were superior to the original formulation (pH 4.5) that was the control. The formulation variant contained BAC-free compositions at pH 4, 4.5 (?,?), Glycerin-free / BAC-free + 0.9% sodium chloride (x), BAC-free + 0.05% sulfite (●, ■).
Figure 10 : Effect of glycerin removal on LACE stability.
Figure 11 : Effect of buffered compositions on LACE stability.
Figure 12a : Correlation of% LACE micelle species as measured by stimulation score and HPLC-UV (in rabbit stimulation model).
Figure 12b : Correlation of% LACE micelle species as measured by stimulation score and HPLC-ELSD (in rabbit stimulation model).
Figure 13 : Glycerol osmolal concentration standard curve.

IV. BRIEF SUMMARY OF THE INVENTION

The present invention achieves the following two main objectives: (a) the production of an ophthalmic solution of LACE stable for at least one year at a refrigeration storage temperature of 2-5 DEG C, and (b) an ophthalmic solution of LACE non- Generation and optimization of process parameters for the manufacture of.

The chemical structure of LACE represents two decomposition points. One is the ring opening of the dithiolane ring and the other is the oxidative and hydrolytic decomposition. As mentioned earlier, LACE interacts with oxygen to rapidly produce oxidized species. LACE in water is prone to lipoic acid and choline by hydrolysis of ester linkages. The rate of hydrolysis is correlated with temperature, and hydrolysis is less at lower temperatures and pH.

LACE ophthalmic solution derivatives, also referred to as EV06 ophthalmic solutions, which were stored in gas permeable, permeable LDPE (low density polyethylene) viscoelastic bottles were studied. Methods developed by the present inventors to minimize oxidation of the LACE solution formulated during storage are described herein.

In addition, extensive compatibility studies of LACE with excipient mixtures have established the importance of certain excipients as stabilizing agents, the role of pH on hydrolytic stabilization of LACE in water, as well as the effects of osmolal concentration-adjusting agents such as sodium chloride and glycerol Respectively. Most importantly, the stabilizing effect of alanine on LACE as opposed to citrate, phosphate and borate is described in the present invention.

Investigating the cause of the irritation, we found that when LACE was dissolved in water, it formed common micelle and micelle aggregates in amphipathic compounds. By definition, the micelle-forming compounds are phosphatidyl choline, PEGylated phosphatidyl choline, PEG-stearate, sorbitol, and the like. Although the micelle formation phenomenon of LACE is not unexpected due to the amphipathic nature of the molecules, the formation of these aggregates at low temperatures was surprising. The presence of the agglomerates was measured by a self-developed RP-HPLC method. The measurement could be performed by both HPLC-UV ( Figure 3a ) and HPLC-ELSD ( Figure 3b ).

The LACE aqueous solution formed a gel-like structure at refrigeration temperature (2-5 ° C). It is also expected that as the concentration of micelle-forming drug increases, the number and aggregation of these micelle assemblies will increase. The present inventors have shown a correlation between the degree of micelle aggregation of LACE and eye surface irritation, and this is an unexpected and surprising result, since micellar vehicles are often considered as drug delivery systems for insoluble compounds. Thus, this was the first report to describe the correlation between stimulus and micelle aggregates. After the discovery, the formulation had to be minimized to show a correlation with comfort.

The formation of micelle aggregates appeared to be correlated with the compounding temperature ( Figure 4 ). The formation of self-assemblies is a thermodynamic phenomenon correlated with an effective reduction of surface free energy to achieve a minimized energy state. When LACE was formulated in low temperature (5 ° C) water, aggregates with the same consistency as the gel were formed. The composition formulated at refrigeration temperature was extremely irritating to the eyes. The agglomerated state can be quantified by the RP-HPLC method (see the chromatogram shown in FIGS. 3A-3B ). By a series of irradiation experiments it was demonstrated that no polymer or oligomer was present when measured by extensive size exclusion chromatography (SEC). Other studies have examined ocular stimuli as a function of the process performed in the presence of ambient air or in the presence of nitrogen. There was no correlation between air or nitrogen stimulation. Both were equally comfortable when formulated at room temperature, but the degradation products were greater in the presence of air. When LACE was compounded at room temperature, micelle aggregation was less when quantified by HPLC method. LACE formulated at room temperature produced a relaxed, non-stimulated solution.

The "loosening" of the micelle aggregates was also unexpected. The agglomerates formed in the LACE aqueous composition could be "pulped" when the solution was equilibrated on the bench at room temperature, as measured by HPLC. Additional experiments suggested deagglomeration was achieved by intense mixing. Thus, these species are not permanent species with covalent bonds, but have proven to be self-assemblies of LACE aggregates that appear to have lower concentrations at room temperature than 5 ° C. The LACE aqueous solutions formed solid viscosities upon freezing. When these solutions were brought to room temperature and stored at this temperature, they again appeared to be homogeneous solutions, which provided additional confidence in the temperature dependence concept of the self-assembly.

However, once incorporated, the agglomerate-free solution of LACE can be stored under refrigeration conditions to minimize oxidative and hydrolytic degradation. Through stability studies, it has been established that the ideal storage temperature of LACE to minimize degradation events is 2-5 ° C.

The ideal blending condition for obtaining a minimal irritant solution was determined to be room temperature (22-25 ° C), and the ideal storage condition for achieving a stable and comfortable LACE ophthalmic solution for presbyopia was determined to be 2-5 ° C.

To further aid stabilization of the ophthalmic solution manufactured from LACE, an oxygen scavenger packet was placed in a mylar impermeable pouch containing an LDPE ophthalmic bottle to prevent oxidation-induced degradation. Extensive stability studies have demonstrated the achievement of one year stability of the EV06 ophthalmic solution.

Embodiments of various compositions for stabilizing LACE, including other types of aqueous agents, such as liposomes, emulsions, blended for the main purpose of stabilizing the drug, are also described herein.

V. DETAILED DESCRIPTION OF THE INVENTION

A. Definition of Terms

The term "EV06", "LACE" or "lipoic acid choline ester" is understood as having the chemical structure shown in Fig.

As used herein, LACE formulations refer to lipoic acid choline ester formulations. For example, a LACE 1.5% formulation refers to a formulation having 1.5% lipoic acid choline ester based on the weight of the formulation. Alternatively, EV06 ophthalmic solution and 1.5% refers to a formulation consisting of 1.5% lipoic acid choline ester.

As used herein, a "derivative" of a lipoic acid choline ester is understood to be any compound or mixture of compounds, other than lipoic acid and choline, formed from the reaction of a lipoic acid cholinester and a non-aqueous pharmaceutical excipient.

As used herein, the term "self-assembly" refers to the thermodynamic assembly of molecules to achieve the most stable energy state. An example of a self-assembly is a micelle formed in water, which is typically formed by a molecule having a hydrophobic component and a hydrophilic component. The hydrophilic component of the molecule is on the surface of the micelle whereas the interior contains a hydrophobic moiety, and in the case of LACE, the choline head group is on the surface of the micelle.

The term "excipient" as used herein refers to a pharmaceutically acceptable excipient, unless the context clearly dictates otherwise.

The term "treating" refers to administering a therapeutic agent in an amount, manner or form effective to ameliorate a condition, symptom or parameter associated with the disease or disorder.

The term "preventing" refers to preventing a patient from having a disability at a statistically significant level or to a degree that can be detected by a typical practitioner, causing the patient to remain unhindered for an extended period of time, or to stop the progression of the disorder .

The term "therapeutically effective amount" refers to an amount of a compound that provides an improvement in the prevention or delay of the onset of an eye disease or disorder (e.g., a presbyopia) in a subject, Quot; refers to the amount of active ingredient (e.g., LACE or a derivative thereof) that provides acquisition of another suitable parameter indicative of < RTI ID = 0.0 >

As used herein, the term "storage stability" or "storage stability" is understood to characterize or characterize a composition or active ingredient (eg, LACE or a derivative thereof) that does not substantially change during storage. Methods of determining such storage stability are known, for example, storage stability may be determined by determining the percentage of the composition or active ingredient (e.g., lipoic acid choline ester) that is retained or degraded in the formulation after storage of the formulation for a particular period of time Can be measured by HPLC. For example, the storage stability pharmaceutical composition may have a stability of at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96% (E.g., 97%, 98%, 99%, or more than 99%) of the active ingredient (e.g., lipoic acid choline ester) is present in the composition.

As used herein, the term compound "relative retention time" or "RRT" is the equation _{"RRT = (t 2 - t} 0) / (t 1 - t 0)" ( wherein, t ₀ = dead time, t ₁ = the residence time of the lipoic acid choline ester, and t ₂ = the residence time of the compound, as determined by HPLC).

As used herein, the term "subject" refers generally to an animal (e.g., a pet) or a human, e.g., a healthy human or a patient with a particular disease or disorder (e.g., presbyopia).

VI. LACE compositions and embodiments

As described herein, the proposed invention provides a pharmaceutical composition comprising a therapeutically effective amount of a lipoic acid choline ester, an excipient, a buffering agent, and a pharmaceutically acceptable carrier, and a method of producing a biocompatible (non-polar), stable solution suitable for ophthalmic eyedrops And embodiments of the process.

The concentration of the lipoic acid choline ester or its derivative in the pharmaceutical composition may be in the range of 0.01-0.1%, 0.1% to 10% of the composition weight (for example, 0.1%, 1%, 2%, 3% %, 6%, 7%, 8%, 9%, 10%, or any range based on these specified numerical values). In some embodiments, the concentration of lipoic acid choline ester in the pharmaceutical composition is 1%. In some embodiments, the concentration of lipoic acid choline ester in the pharmaceutical composition is 3%. In some embodiments, the concentration of lipoic acid choline ester in the pharmaceutical composition is 4%. The preferred range of LACE in the composition is 1-3%. Within this range, the preferred composition range is 1.5-4%.

In another embodiment, the composition effective in the proposed invention is an aqueous formulation containing LACE and alanine, wherein the alanine has a concentration of 0.1-0.5%, 0.5% -1%, 1% -1.5%, 1.5% -3% . Within this range, the preferred composition is 0.5% alanine and 1.5% LACE.

In a preferred embodiment, the effective LACE and alanine-containing compositions contain benzalkonium chloride at a concentration of 30-150 ppm as a preservative.

In another embodiment, other preservatives, such as polyquaternium, SofZia, are included in the LACE aqueous formulations at an approved concentration for human use by the FDA as a preservative. Other preservatives may be 2-phenylethanol, boric acid, disodium edetate.

In another embodiment, the LACE-containing ophthalmic solution is a single volume sterile product without preservative.

The method of making biocompatible solutions may be encapsulation into liposomes, since the self-assembled micellar solution of LACE dissolved in water at high concentration may exhibit some irritation. In this case, LACE will be contained inside the liposome. Liposomes are generally ocular surface and biocompatible.

In another embodiment, the pharmaceutical composition has glycerol at a concentration of 0.1% -10%. In a preferred embodiment, the composition has a glycerol concentration of 0.1-5%.

In some embodiments, the preservative is benzalkonium chloride and the biochemical source of energy is alanine. In some embodiments, the lipoic acid choline ester is selected from the group consisting of chloride, bromide, iodide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, hydrogen fumarate, tartrate (+) - tartrate, (-) - tartrate, or a mixture thereof), an anion of an amino acid such as bitartrate, succinate, benzoate, and glutamic acid.

Suitable buffers capable of achieving a desired pH (e. G., Described herein) for a pharmaceutical composition may be any of those known in the art. Non-limiting examples include phosphate buffers (e.g., sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydride), acetate buffers, citrate buffers, borate buffers, and HBSS (Hank balanced salt solutions) . The appropriate amount of buffer can be readily calculated based on the desired pH. In any of the embodiments described herein, the buffer is used in an amount acceptable as an ophthalmic product. However, in some embodiments, the pharmaceutical composition does not comprise a buffer. In some embodiments, the pH of the aqueous solution or the final pharmaceutical composition is adjusted to a desired pH range (e.g., described herein) using an acid (e.g., hydrochloric acid) or a base (e.g., sodium hydroxide) do.

In another embodiment, the buffer system may be selected from borate buffers, phosphate buffers, calcium buffers, and combinations and mixtures thereof. In a preferred embodiment, the buffer is an amino acid buffer. In another preferred embodiment, the amino acid buffer is comprised of alanine.

In some embodiments, the lipoic acid choline ester is selected from the group consisting of chloride, bromide, iodide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, hydrogen fumarate, tartrate (+) - tartrate, (-) - tartrate, or a mixture thereof), an anion of an amino acid such as succinate, benzoate, and glutamic acid. Other counterions are stearate, propionate and furoate.

In some embodiments, the ophthalmic dosage form has a pH of from 4 to 8. In some embodiments, the ophthalmic formulation has a pH of 4.5. In some embodiments, ophthalmic formulations comprise at least one component selected from the group consisting of biochemically acceptable energy sources, preservatives, buffers, thickening agents, surfactants, viscosity modifiers, and antioxidants.

In some embodiments, the pharmaceutical composition contains an antioxidant. In some preferred embodiments, the antioxidant is comprised of ascorbate. In another preferred embodiment, the antioxidant contains glutathione. Suitable antioxidants may be any of those known in the art. Non-limiting examples include ascorbic acid, L-ascorbic acid stearate, alpha thioglycerin, ethylenediaminetetraacetic acid, erythorbic acid, cysteine hydrochloride, N-acetylcysteine, L-carnitine, citric acid, tocopherol acetate, Sodium thioglycolate, natural thiomalate, natural vitamin E, tocopherol, ascorbyl palmitate, sodium lauryl sulfate, sodium lauryl sulfate, sodium lauryl sulfate, (3,5-di-t-butyl-4-hydroxyphenyl)] propionate, propyl thiourea, propyl thiourea, Galactate, 2-mercaptobenzimidazole and oxyquinoline sulfate. Suitable amounts of the antioxidant may range from 0.1% to 5% (e.g., 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5% Any range). In any of the embodiments described herein, the antioxidant is used in an amount acceptable for ophthalmic use.

In some embodiments, the pharmaceutical composition is prepared by combining in an inert environment, such as high purity nitrogen or argon. In a preferred embodiment, the pharmaceutical composition is formulated in a nitrogen environment with less than 2 ppm oxygen.

In some embodiments, the pharmaceutical composition is prepared by combining at a temperature of 20-25 占 폚.

In a preferred embodiment, the solid LACE molecules are pulverized into fine powder. Preferably, the solid LACE molecules are pulverized into a lumpless powder. In one embodiment, the particle size will be less than 500 micrometers. In another preferred embodiment, the particle size will be less than 100 micrometers.

In a preferred embodiment, the pharmaceutical composition is prepared by initial deaeration of an aqueous solution maintained at room temperature (20-25 DEG C), then dissolving the excipient in the solution, then adding solid LACE in portions .

In one embodiment, the pharmaceutical composition is vigorously agitated for 4 to 24 hours. In a preferred embodiment, the pharmaceutical composition is vigorously agitated for 4 to 8 hours. In another preferred embodiment, the pharmaceutical composition is vigorously stirred for 8 hours.

The pharmaceutical compositions produced by these methods can have storage stability of at least 3 months (e.g., 3 months, 6 months, 9 months, 1 year, or more than 1 year).

The pharmaceutical composition may also have an advantageous profile of the drug-related degradation product (e.g., the total drug-related impurity, or the amount of certain drug-related impurities) after storage for a certain period of time at 5 ° C. Analytical tools (e. G., HPLC) for determining the amount of drug-related degradation in a formulation are known.

Suitable biochemically acceptable energy sources may be any of those known in the art. For example, a biochemically acceptable energy source may be any that can facilitate reduction by participating as an intermediate of the energy metabolism pathway, particularly the glucose metabolism pathway. Non-limiting examples of suitable biochemically acceptable energy sources include amino acids or derivatives thereof (e.g. alanine, glycine, valine, leucine, isoleucine, 2-oxoglutarate, glutamate, and glutamine) (E. G., A fatty acid or a salt thereof), such as water (e. G. Glucose, glucose-6-phosphate (G6P)), pyruvate (e.g. ethyl pyruvate), lactose, lactate, Derivatives such as mono-, di-, and tri-glycerides and phospholipids), and others (e.g., NADH). Suitable amounts of the biochemically acceptable energy source may range from 0.01% to 5% (e.g., 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4% , Or any range based on these specified numerical values). In some embodiments, the biochemical energy source is ethyl pyruvate. In some embodiments, the biochemical energy source is alanine. In some embodiments, the amount of ethyl pyruvate or alanine is in the range of 0.05% to 5% (e.g., 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3% , 5%, or any range based on these specified numerical values). In some embodiments, the amount of alanine is 0.5% by weight of the composition. In any of the embodiments described herein, the biochemically acceptable energy source is used in an amount acceptable for ophthalmology.

Suitable preservatives may be any of those known in the art. Non-limiting examples include benzalkonium chloride (BAC), seturonium, chlorobutanol, EDTA, polyquaternium-1 (Polyquad®), polyhexamethylenebiguanide (PHMB ), Stabilized oxychloro complexes (PURITE®), sodium perborate, and SOFIA®. A suitable amount of preservative in the pharmaceutical composition may be in the range of 0.005% to 0.1% (e.g., 0.005, 0.01, 0.02%, 0.05%, 0.1%, or any range based on these stated numerical values) have. In some embodiments, the preservative is benzalkonium chloride. In some embodiments, the benzalkonium chloride is present in an amount ranging from 0.003% to 0.1% by weight of the composition (e.g., 0.003, 0.01, 0.02%, 0.05%, 0.1%, or any range ). In some embodiments, the benzalkonium chloride is used in an amount of 0.01% by weight of the composition. In any of the embodiments described herein, the preservative is used in an amount acceptable for ophthalmic use. In some embodiments, the pharmaceutical composition does not contain a preservative.

Suitable thickening agents may be any of those known in the art. Non-limiting examples include sodium chloride, potassium chloride, mannitol, dextrose, glycerin, propylene glycol, and mixtures thereof. A suitable amount of a thickening agent in the pharmaceutical composition is any amount capable of achieving an osmolal concentration of 200-460 mOsm (e.g., 260-360 mOsm, or 260-320 mOsm). In some embodiments, the pharmaceutical composition is an isotonic composition. In some embodiments, the amount of the thickening agent (e.g., sodium chloride) is from 0.1% to 5% (e.g., 0.1%, 0.5%, 1%, 2%, 3%, 4% Or any range based on these specified numerical values). In any of the embodiments described herein, the barrier is used in an amount acceptable for ophthalmic use.

Suitable surfactants, including ionic surfactants and nonionic surfactants, may be any of those known in the art. Non-limiting examples of useful nonionic surfactants include polyoxyethylene fatty esters such as polysorbate 80 [poly (oxyethylene) sorbitan monooleate], polysorbate 60 [poly (oxyethylene) sorbitan Poly (oxyethylene) sorbitan monopalmitate], poly (oxyethylene) sorbitan monolaurate, poly (oxyethylene) sorbitan trioleate, or polysorbate 65 [ Polyoxyethylene hydrogenated castor oil, poly (oxyethylene) sorbitan tristearate), polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, Oxyethylene hydrogenated castor oil 60), polyoxyethylene polyoxypropylene glycol (e.g., polyoxyethylene (160) polyoxypropylene (30) Recall [Pluronic F681], Polyoxyethylene (42) Polyoxypropylene (67) Glycol [Pluronic P123], Polyoxyethylene (54) Polyoxypropylene (39) Glycol [Pluronic P85] , Polyoxyethylene (196) polyoxypropylene (67) glycol [Pluronic F1271], or polyoxyethylene (20) polyoxypropylene (20) glycol [Pluronic L-441], polyoxyl 40 stearate , Sucrose fatty esters, and combinations thereof. In some embodiments, the surfactant is polysorbate 80. Suitable amounts of surfactant in the pharmaceutical composition may range from 0.01% to 5% (e.g., 0.05, 0.1, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5% And any range based on the specified numerical value). In some embodiments, the surfactant is polysorbate 80 and the amount of polysorbate 80 is in the range of 0.05% to 5% (e.g., 0.05, 0.1, 0.2%, 0.5%, 1% , 3%, 4%, 5%, or any range based on these specified numerical values). In some embodiments, the amount of polysorbate 80 is 0.5% by weight of the composition. In any of the embodiments described herein, the surfactant is used in an amount acceptable for ophthalmic use. However, in some embodiments, the pharmaceutical composition does not contain a surfactant.

Suitable viscosity modifiers may be any of those known in the art. Non-limiting examples include, but are not limited to, carbopol gels, celluloses (e.g., hydroxypropylmethylcellulose), polycarbophil, polyvinyl alcohol, dextran, gelatin glycerin, polyethylene glycol, Poloxamer 407, polyvinyl alcohol and polyvinyl Pyrrolidone, and mixtures thereof. A suitable amount of viscosity modifier may be in the range of 0.1% to 5% (e.g., 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5% Any range). In any of the embodiments described herein, the viscosity modifier is used in an amount acceptable for ophthalmic use. In some embodiments, the pharmaceutical composition does not contain a viscosity modifier (e. G., A polymeric viscosity modifier such as hydroxypropylmethylcellulose).

In some embodiments, the pharmaceutical composition is characterized by one or more of the following:

(a) the concentration of the lipoic acid esters of from 0.1% to 10% of the weight of the composition (e.g., any range between 0.1%, 1.0%, 1.5%, 3%, 4%, 5%, or specified numerical values) ;

(b) has a concentration of from 0.003% to 0.1% (e.g., 0.01%) of a preservative agent (e.g., benzalkonium chloride) by weight of the composition;

(c) has a biochemical energy source (e.g., alanine) from 0.1% to 5% (e.g., 0.5%) by weight of the composition; And

(d) a concentration of glycerol of from 0.5% to 5% (e.g., 2.7%) by weight of the composition.

In some embodiments, the pharmaceutical composition consists essentially of 1-3 wt% glycerin, 0.5 wt% alanine, 0.005-0.01 wt% benzalkonium chloride, 1-3 wt% lipoic acid choline ester, and water, The pH of the pharmaceutical composition is 4.3 to 4.7.

In one embodiment, the ophthalmic composition is administered once a day, twice a day, three times a day, and four times a day to each eye of a subject.

In some embodiments, the present invention also provides a system for storing a pharmaceutical composition comprising an active component (e.g., a lipoic acid choline ester or derivative thereof) that is susceptible to hydrolysis in an aqueous solution in an aqueous solution. In a preferred embodiment, the pharmaceutical composition is stored in an LDPE ophthalmic ointment bottle that is overlaid and capped with nitrogen during the filling process and then packaged in a secondary mylar-impermeable pouch containing an oxygen absorbent.

In another embodiment, the pointee bottle or unit is polyethylene terephthalate (PET). In another embodiment, the pointee bottle is made of a material having a low gas permeability.

In another embodiment, the viscoelastics can be made of any material with low gas permeability. In another embodiment, the pointee bottle may be a unit volume filled by blow molding fill seal technology.

In one embodiment, the pharmaceutical composition is stored at 2-5 [deg.] C for a period of 3 months to 2 years.

VII. Treatment method

A pharmaceutical composition comprising a lipoic acid choline ester or a derivative thereof (e.g., as described herein) may be used in a method of treating or preventing a disease or disorder associated with oxidative damage. Diseases or disorders associated with oxidative damage are known.

In some embodiments, the invention provides a method of treating an eye disease in a subject, comprising administering a therapeutically effective amount of any of the pharmaceutical compositions described herein to the eye of a subject in need thereof.

In some embodiments, the ocular disease is ocular disease, dry eye syndrome, cataract, macular degeneration (e.g., age-related macular degeneration), retinopathy (e.g., diabetic retinopathy), glaucoma, or ocular inflammation. In some embodiments, the eye disease is presbyopia.

The amount of the pharmaceutical composition suitable for the treatment or prevention of ocular diseases herein may be any therapeutically effective amount. In some embodiments, the method includes adjusting the perspective adjustable size of the lens by at least 0.1 diopter (D) (e.g., 0.1, 0.2, 0.5, 1, 1.2, 1.5, 1.8, 2, 2.5, 3, or 5 diopters) In the eye of the subject. In some embodiments, the method comprises administering 1-5 drops (about 40 [mu] L / drop) of the pharmaceutical composition to the eye of the subject. In some embodiments, the subject's eye is treated with the pharmaceutical composition once daily, once, twice, three times, four times, five times, or more than once per day as 1-5 drops (about 40 μL / drop). In some embodiments, the lens or eye of the subject is treated with a pharmaceutical composition at a rate of 1, 2, 3, 4, 5, or more than 5 times each time. In some embodiments, the eye of the subject is treated with the pharmaceutical composition of the present invention once or twice a day, once or twice daily (about 40 [mu] L / drop).

The methods include prophylactic methods that can be performed on patients of any age. The method also includes a therapeutic method that can be performed on patients of any age, particularly those between 20 and 75 years of age.

The following examples illustrate claimed embodiments and are not intended to limit the scope thereof.

Example

Example 1

Table 1 : General properties of lipoic acid choline ester (LACE)

Example 2

Correlation Between Dynamics of Micelle Species and Mixing Time of LACE Process Solution

The experiments described in this section demonstrate that LACE micelles are stabilized and reduced as the mixing time is extended at 25 ° C. As a result, the reversible nature of these species has been demonstrated, which is characterized by self-assembled systems such as micelle and micelle aggregates.

The micelle species formed by spontaneous self-assembly of molecules were induced by the total free energy of the equilibrated system. This experiment demonstrated the kinetics of achieving the equilibrated state by a longer mixing time.

Goal :

Establish a process-time layer by establishing that the growing micelle species has stabilized.

o Establish a "holding time".

step:

o After oxygen is removed from the vehicle by bubbling with nitrogen, two of 1.5% LACE A 200-g batch was prepared at 25 占 폚. Nitrogen was bubbled continuously during the dissolution of LACE.

One batch was prepared using intact lumps of GMP batch # 2 (G2-14LAC), and the other batches were prepared using a G2-14LAC sample ground into fine powder using a mortar and pestle.

o After dissolving the LACE and adjusting the pH, the batch was stirred for 24 hours under a constant nitrogen overlay while maintaining the dissolved oxygen content at ~ 1.6 ppm (about 8.2 ppm saturation solubility). At the time of 1h, 3h, 4h, 6h, 8h, 9h and 24h, approximately 5-15 mL was removed by syringe and sterile filtered into a bottle with a nitrogen vial (5 mL / bottle) Used for bulk placement).

o Samples at all time points were diluted to 10 mg / g and then injected for RP-HPLC analysis by ELSD detection within 30 minutes of removal from the bulk solution.

o After 24 hours, the bulk solution was sterile filtered and divided into two ~ 50 mL portions, one at 5 ° C and another 50-mL portion at 25 ° C. All portions were overlaid with nitrogen blown into the vessel.

o At the end of the additional 24 hour hold time, each section was filled into the bottles with overlaying nitrogen into the bottle.

Observation on dissolution

o The lump of G2-14LAC was added to the formulation KW-LACE-01-86-1 over about 5 minutes, and some lumps needed to be dissolved for an additional 20 minutes.

o Powdered G2-14LAC was added to the formulation KW-LACE-01-86-2 over a period of about 15 minutes, since the amount of each spatula aggregated into a thin suspension of material floating on the surface, It is because it did not. Thus, no further portion was added until the previous portion was attracted to the vortex. The time for any one part to dissolve was estimated to be about 10 minutes, and the entire process took about 25 minutes.

result

Peak at RT = 8 min (correlated with micelle species) was evident in both formulations taken at the first time point.

o The second batch made with powdered LACE had higher levels of micelle species at some point, but there was no consistent difference between the two batches in the% area of the 8 minute peaks (micelle species).

o The% area of the 8 min peak was significantly reduced at 24 hours as shown in the table below.

The final pH for both batches was 4.54.

Table 2 :

Dynamics of formation and deaggregation of LACE micelle species by long time mixing

As a result, it was proved that the mixing time was prolonged to minimize the LACE micelle species at 8.1 minutes. The 8.1 min peak was dramatically reduced with increasing mixing time.

Each solution was also assayed for degradation products of lipoic acid cholinesterase. As mentioned earlier, the degradation mechanism of LACE is both oxidative and hydrolytic, producing oxidized and hydrolyzed species.

Table 3 :

Analysis of impurities (related substances) in the EV06 ophthalmic solution as a function of mixing

The data suggest that the degradation products of LACE increased as the mixing time was extended. Thus, the final process conditions for blending the EV06 ophthalmic solution with the solution to achieve a non-magnetic solution with minimized degradation were up to 8 hours.

Example 3

Correlation between Mixing Temperature and Presence of Micellar LACE Species

The data presented in Figure 4 is a solution of LACE chloride formulated under argon and refrigeration conditions. The solution was extremely irritating to the ocular surface. Percent micelle species were the main LACE API peaks at 8-10% (micelle species are indicated by arrows at retention time 7.9-8.1 min), which is a concentration not normally observed in mixed solutions at room temperature.

Example 4

Correlation of lumps against micelle LACE species formation

5A is RP-HPLC chloride chromatogram of the EVO6 ophthalmic solution prepared from the LACE batch with solid "lumps ". The solution prepared from the API of the lot (active pharmaceutical ingredient, solid LACE drug substance) showed a higher percentage (10-15%) of the micellar LACE species (indicated by the arrows) compared to the solution made from the powdered API lot ( Figure 5b ) Respectively. Thus, both of the solutions appeared to be completely dissolved, but the solution formulated from the lumpless API had a lower concentration of micellar LACE species. In correlation with eye irritation, the solution presented in FIG. 5A had a higher score for irritation in the rabbit model. This led to the introduction of lump removal procedures to make the powdered material before compounding.

Example 5

Study of compatibility of excipient with LACE

summary

The purpose of these experiments was to identify possible destabilization parameters in the formulation through systemic changes in formulation and microenvironment (e.g. pH). Lipoic acid and any derivatives of lipoic acid are subject to decomposition and polymerization by heat, light and oxygen and are prone to ring opening of the dithiolane ring. Thus, the presence of an excipient that can lead to oxidative free radical cleavage can be a destabilizing factor. Formulation grids 1 and 2 systematically examined the effects of excipients already present in the formulation as possible destabilizing factors.

In these experiments, the formulation of LACE was diluted with 1 N sodium hydroxide or 1 N hydrochloric acid added to achieve a pH of 4.4-4.6 and an osmolal concentration of 290-300 mOsm / kg, and the drug substance, alanine, glycerin, Lt; / RTI > The experiments described herein were a study of compatibility to identify excipients that could stabilize the LACE ophthalmic solution.

Formulation Grid # 1 was tested for the following variables shown in (a) - (e). The formulation was made in a nitrogen-flushed glove box and sterile filtered. All formulations were tested under accelerated conditions at < RTI ID = 0.0 > 57 C < / RTI > and tested by HPLC at T = 0, 3.5 and 7 days for assays and impurities. All 19 formulations were tested on grid # 1.

(a) Effect of pH: Formulations were prepared at pH 3.5, 4 and 5 and compared to control formulations at pH 4.5. As shown in Figure 6 , the degradation rate of LACE was equivalent at all pH levels of 3.5-5.

(b) Effect of alanine: The role of alanine in the formulation was derived by comparing the rate of degradation with the original formulation (control). As shown in Figure 6 , the absence of alanine was considered to accelerate the rate of degradation of LACE. Thus, alanine is an important excipient in EV06 ophthalmic formulations.

(c) Effect of benzalkonium chloride and glycerin : Peroxides contained in glycerin were assumed to be able to catalyze oxidation, and similarly, due to free radical cleavage and subsequent oxidation, BAC could inactivate the drug substance . As shown in FIG . 7 , the benzalkonium chloride-free formulations were substantially more stable than the control. The glycerin-free sample was also more stable than the control. Additionally, sodium chloride added to the formulation (instead of glycerol, to adjust the osmolal concentration) was considered to have a destabilizing effect (also shown in FIG. 7 ). In another experiment with various combinations of glycerin, sodium chloride, sulfite and pH, all with changes of benzalkonium chloride, it was noted that all the benzalkonium chloride-free formulations were more stable than the control group (Fig. 5). The experiments in Figures 7 and 9 demonstrate that removal of benzalkonium chloride in LACE can stabilize the formulation. For EV06 ophthalmic compositions, minimizing the benzalkonium chloride content to 50 ppm may have a major stabilizing factor. Sodium chloride showed a destabilizing effect, and therefore glycerol was considered more suitable as a wall agonist in the final EVO6 composition.

(d) Effect of sulfite : Various experiments were carried out using sulfite by combination of various levels of sulfite ( Fig. 8 ). Sulfite as an antioxidant was added to the formulation at various pH levels (4, 4.5) and concentrations ( Figure 8 ). The presence of sulfite did not appear to substantially improve the stability of LACE. Since 0.1% sulfite in the formulation was equivalent to that of the control group, it was not clear whether or not the harmful effect was present.

(e) Effect of glycerin : The effect of glycerin was investigated by systematic removal of glycerin from various combinations of formulations. As shown in Figures 7 and 10 , the glycerin-free combination appeared to be more stable than the control. However, due to the high destabilizing effect of sodium chloride, glycerin has been selected as an important excipient for wall thickening.

(f) Effect of buffer: Various buffered compositions were tested. Acetate buffer and acetate + boric acid appeared to stabilize the formulation.

Experiment

a) HPLC Method Setup : The HPLC assay was (A) adjusted to pH 4.5 with 0.05 M sodium phosphate monobasic, 0.005 M sodium 1-heptanesulfonate, 0.2% v / v triethylamine, phosphoric acid; And (B) acetonitrile. The analytical column used was YMC pack ODS AQ (4.6 x 250 mm, 5 탆, 120 Å), P / N AQ 125052546WT and the analytical detection wavelength was 225 nm.

b) Formulation

The formulations were prepared with care to ensure that the LACE API was not exposed to oxygen or heat. The API was aliquoted into clean glass vials under an inert N ₂ atmosphere inside a glove bag and wrapped in tin foil in a -20 ° C freezer until use. The formulations were prepared using high purity excipients and sterile glassware. All excipients were previously prepared as stock solutions and mixed together prior to API addition & final pH adjustment. Formulations are summarized in Appendix A.

II. Results and discussion

Figure 6 shows the results of a comparison of the% LACE API versus the non-alanine-free control formulations prepared formulations at pH 3.5, 4, 4.5 (original), 5 over days at T = 0, 3.5, ). Even at T = 0, alanine-free formulations had significant degradation in API content. As shown in Figure 6 , the formulations were equivalent under these conditions at pH 3.5-5. Figure 7 is a plot of a formulation comparing the following variables: (a) control (original) versus control + 0.25% sodium chloride, control + 0.25% sodium chloride, glycerin free; (b) control (original) versus benzalkonium chloride (C) control (original) vs. glycerin-free original formulation.

As shown in Figure 7 , the addition of sodium chloride to the original formulation did not stabilize the formulation.

Figure 8 shows the effect of sulfite on LACE stability at < RTI ID = 0.0 > 57 C. < / RTI > Sulfite-containing formulations were prepared at pH 4 and 4.5 at concentrations of 0.05% sulfite (?,?) And 0.1% sulfite (x). The sulfite addition did not stabilize the original formulation ().

Figure 9 further analyzes the potential stabilizing effect of benzalkonium chloride removal. All formulation variants that did not contain benzalkonium chloride were superior to the original formulation (pH 4.5) that was the control. The formulation variant contained BAC-free compositions at pH 4, 4.5 (?,?), Glycerin-free / BAC-free + 0.9% sodium chloride (x), BAC-free + 0.05% sulfite (●, ■).

Figures 7 and 10 compare the effect of glycerin removal on various compositions as a function of pH, sulfite and sodium chloride. The glycerin-free, BAC-free, and glycerin-free, BAC-containing formulations (*) in the presence of sodium chloride and sulfite (+) were superior to the original formulation (*).

Figure 11 investigated the use of various buffered compositions for LACE stability. The original formulation (pH 4.5) was compared with the acetate buffer composition (I, x, *,) and the borate of pH 7.5. Sodium edetate added as an antioxidant did not stabilize the formulation. Acetate buffer and acetate buffer + boric acid appeared to be superior to the control formulations.

In summary, the removal of benzalkonium chloride has been shown to consistently improve stability. Removal of glycerol can also be a positive step. Glycerol is sometimes known to retain formaldehyde, which results in API degradation. Interestingly, the addition of edetate or sulfite did not have a positive effect. Another antioxidant, such as sodium ascorbate, can have a positive effect.

Table 4 :

Compatibility Formulation

Example 6 :

Correlation between eye irritation and percent micelle LACE species

Figures 12a and 12b generally provide a snapshot of the correlation of stimulus and micellar LACE species for a number of compounding batches.

Example 7

How to adjust the osmolal concentration using glycerol

The osmolal concentration range required for drug-containing formulations and placebo is 280-320 mOsm / kg. Preferably, all LACE formulations need to be within 290-310 mOsm / Kg.

Because LACE contributes to the osmolal concentration, each formulation will have varying concentrations of glycerol to achieve the required osmolal concentration.

I. Summary: The final adjusted composition

Table 5 :

The final composition of EV06 ophthalmic solution with adjusted glycerol concentration

II. Experiment details:

A. Glycerol-containing placebo

A series of placebo was prepared. All placebo, and the subsequently prepared LACE-containing solution, contained the following ingredients with varying amounts of glycerol:

ㆍ 0.5% (5 mg / g) alanine

0.005% (0.05 mg / g) benzalkonium chloride

A small amount of 1 N sodium hydroxide, 1 N hydrochloric acid, to adjust the pH to 4.5

ㆍ Water for injection (added for final weight)

Table 6 :

Glycerol-containing placebo (effect of glycerol concentration)

B. LACE-containing formulations

A series of solutions were prepared based on the above glycerol osmolal concentration standard curve (see Table 6) and on the observations of the Applicant which presented an additional 44-55 mOsm / kg (average 48 mOsm / kg) per 1% LACE, The actual osmotic contribution of LACE was confirmed. The target for total osmolal concentration was 300 mOsm / kg.

Table 7 :

The glycerol concentration for the EV06 composition

These data show that the effect of LACE on the osmolal concentration is somewhat better than expected at 57-60 mOsm / kg per 1%. Thus, a series of whole solutions were prepared with a slightly modified target osmolal concentration for LACE-free solutions, and thus with different target glycerol contents. All solutions were prepared using the same alanine / benzalkonium chloride, pH 4.5 stock solution as used in the placebo, so that the final composition was consistent:

0.5% (5 mg / g) alanine

0.005% (0.05 mg / g) benzalkonium chloride

A small amount of 1 N sodium hydroxide, 1 N hydrochloric acid, to adjust the pH to 4.5

Water for injection (added for final weight of 5.0 g per formulation)

Table 8 :

Adjustment of osmolal concentration of EV06 composition

C. Sterile Manufacturing

Based on these experimental results, a sterile filtered 10.0-g batch of each formulation was made with the following composition and the sterile eyedrop was packaged in bottles (2 mL / bottle):

Table 9 :

The final composition grid of EV06 composition

Example 8

Method for producing LACE pharmaceutical composition

The method of preparing the LACE pharmaceutical composition is as follows:

o At room temperature, water for injection (WFI) was added to the glass formulation vessel at 80% of the batch weight. Water was purged with nitrogen to achieve ≤ 10 ppm oxygen.

o Alanine, glycerin and BAC were added stepwise and mixed until dissolved.

The pH was adjusted to 4.4 - 4.6 with HCl or NaOH.

o LACE was ground in a mortar and pestle under nitrogen to remove lumps and added slowly during mixing.

o An oxygen scavenging water was added to achieve the final batch target weight.

o batches were mixed for a total of 8 hours to ensure complete dispersion and dissolution.

o The pH can be adjusted to 4.4 - 4.6 with NaOH or HCl if necessary.

o The osmolal concentration can be adjusted to 290-310 by glycerol if necessary.

After mixing for 8 hours, the EV06 bulk drug product solution was aseptically filtered through a holding bag through a capsule SHC 0.5 / 0.2 μm sterile filter.

o The bulk product solution in the holding bag was maintained at 5 占 폚 by refrigeration or ice bath.

o Filtration bubble point tests were performed to ensure the integrity of the filter.

o The sterile filtered bulk solution was aseptically transferred to a Class 100 room and filled into a pre-sterilized bottle.

o Sterilization tips and caps were applied to the bottles under a nitrogen overlay.

o The sealed bottle was transferred to a tray and the tray was placed in a bag under nitrogen purge and immediately transferred to a 5 ° C storage.

Example 9

Stability study of LACE formulation

The initial formulation samples contained sodium edetate and 0.01% benzalkonium chloride. These excipient-containing and no-containing stability studies have demonstrated that sodium edetate does not stabilize LACE. The presence of excessive amounts of benzalkonium chloride caused some destabilization of the drug. Thus, the final formulation did not contain sodium edetate and contained 0.005% benzalkonium chloride. Microbiological tests have shown that 0.004% benzalkonium chloride in the present formulation composition is effective as a preservative in drug products.

In an effort to further stabilize the drug formulation, systematic stability studies (5 < 0 > C, 25 [deg.] C and 40 [deg.] C) for medium scale R & D batches were conducted with the presence and absence of oxygen scavenging packets contained in zippered steam impervious foil pouches Was carried out using bottled EV06 ophthalmic solution. A bottle of product stored at 5 DEG C in the presence of an oxygen scavenging packet sealed in a resealable foil pouch proved 12 months of stability.

Additional precautions were taken in the course of the process to stabilize the final formulation from exposure to ambient oxygen and degradation due to non-chilled conditions. The handling of the drug substance under nitrogen (exclusion of oxygen and minimization of water) and formulation under nitrogen blanket were performed to minimize exposure to oxygen. After compounding, the product was filled into a water vapor impermeable holding bag and stored under refrigeration conditions until bottled. The holding bag containing the bulk solution was kept at low temperature during charging. Nitrogen blanket was placed on each bottle of drug solution to minimize nitrogen exposure.

Table 10 : Stability of EV06 ophthalmic solution (3.0%)

Claims (15)

0.1 to 10% by weight of a pharmaceutically acceptable salt of a lipoic acid cholinesterase, 0.1 to 2% by weight of a barrier regulator, 0.003 to 0.01% by weight of a preservative, 0.05 to 1.0% by weight of a biochemical energy source, A pharmaceutical composition for the treatment of presbyopia. 2. The composition of claim 1 wherein the pharmaceutically acceptable salt of the lipoic acid choline ester is a chloride, bromide or iodide salt. 3. The composition according to claim 1 or 2, wherein the long-acting adjuvant is glycerol. 4. The composition according to any one of claims 1 to 3, wherein the preservative is benzalkonium chloride. 5. The composition according to any one of claims 1 to 4, wherein the biochemical energy source is alanine. 6. The composition of any one of claims 1 to 5 having storage stability of at least 3 months, at least 6 months, at least 9 months or at least 1 year. 7. The composition according to any one of claims 1 to 6, wherein the composition is a non-polarizable eye drop solution. A method of preparing a pharmaceutical composition according to any one of claims 1 to 7, comprising:
Finely pulverizing a pharmaceutically acceptable salt of a lipoic acid choline ester,
Adding the ground salt to water having less than 5 ppm, preferably less than 2 ppm oxygen,
For 6 to 8 hours, preferably 8 hours at room temperature to form a mixture,
Filling the ophthalmic bottle with the mixture, adding an inert gas overlay before capping,
Packaging the filled and capped ophthalmic bottle in a gas-impermeable pouch, and
Store the package at 2-8 ° C. 9. The method of claim 8, wherein the pouch contains an oxygen scavenger. 10. The method according to claim 8 or 9, wherein the pharmaceutically acceptable salt of the lipoic acid cholinester is pulverized into a powder having an average particle size of 5 mm or less. 11. The process according to any one of claims 8 to 10, wherein the mixing temperature is from 20 to 25 占 폚. 12. The process according to any one of claims 8 to 11, wherein the inert gas is nitrogen. 13. The method according to any one of claims 8 to 12, wherein the ophthalmic bottle is low density polypropylene (LDPE), polyethylene terephthalate (PET) or polytetrafluoroethylene (PTFE). 14. A method according to any one of claims 8 to 13, wherein the ophthalmic bottle is a blow-molding-filling-sealing unit. 14. A storage stability and / or non-irritating eyedrops solution prepared by the method of any one of claims 8 to 14.

Images